tbuckley/cabot-search huggingface dataset:
Abstract 70: Mechanisms of tumor dormancy induction mediated by abrogation of myeloid tgfβ signaling
Authors: Abdul Ahad, Feng Leng, Hiroshi Ichise, Justin Gray, Olga Aprelikova, Maura O’Neill, Ronald Holewinski, Vishal N. Kopardé4, Yasuhiro Moriwaki, Christine Hollander, Ronald Germain, Thorkell Andresson, Yang Li
Journal: Cancer Research (2023)

Abstract Persistence in a dormant state of residual tumor cells can occur following extended periods of clinical remission which may last decades. The disseminated tumor cells in distant organ sites eventually gain context dependent metastasis advantage during tumor progression. The mechanisms for dormancy induction or reactivation remain unclear. We found that the abrogation of myeloid TGF-β signaling induced tumor dormancy in breast cancer metastasis models. When given extended time, the TGFβRIImyeKO mice eventually developed similar number of metastatic nodules to that of control mice. We further validated our finding using an inducible system where reintroduction of TβRII diminished the tumor dormancy induction. RNAseq of dormant vs proliferative tumor cells identify 504 differential expressed genes, including those involving cell cycle arrest, IFNg response, MTOR signaling as well as MYC targeted genes. Immune cell profiling showed differential immune composition in micro and macro-tumor microenvironment between WT and TβRIImyeKO lung tissues. Of great interest, abrogation of myeloid specific TGF-β signaling increased the number of CD103+DCs that displayed elevated TNFa production, which in turn increased IFNg+ production in T cells leading to improved innate and adaptive immunity. Importantly, depletion of CD103 DCs in tumor-bearing TβRIImyeKO mice diminished the dormancy phenotype, which was not observed for the pDC depletion in the WT control mice. These data demonstrate that abrogation of myeloid specific TGF-β signaling improved the immune microenvironment, which induced tumor dormancy. Our data provide mechanistic insight and resources to understand the tumor dormancy. Citation Format: Abdul Ahad, Feng Leng, Hiroshi Ichise, Justin Gray, Olga Aprelikova, Maura O’Neill, Ronald Holewinski, Vishal N. Kopardé4, Yasuhiro Moriwaki, Christine Hollander, Ronald Germain, Thorkell Andresson, Yang Li. Mechanisms of tumor dormancy induction mediated by abrogation of myeloid tgfβ signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 70.
Abstract 356: Targeting differential metabolism in an aged model of cancer cachexia
Authors: Aneesha Dasgupta, Rebecca E. Schmitt, Jessica Z. Schneider, Tatsuyoshi Kono, Chih-Chun Lee, Carmella Evans-Molina, Jason D. Doles
Journal: Cancer Research (2023)

Abstract Cancer cachexia is a multifactorial syndrome entailing muscle and fat wasting, inflammation, and metabolic dysfunction. Pancreatic cancer has the highest incidence of cachexia at around 80%. However, there are no FDA approved therapy for cachexia in the clinic yet. This is mostly because of the failure of preclinical therapies to demonstrate success in the clinic. Most preclinical studies utilize 6-8 week old mice which roughly corresponds to a human age of ~ 20 years. However, the median age of diagnosis of pancreatic cancer is ~70 years. Given widespread physiology, microenvironment, and metabolism differences in young and aged skeletal muscle, we sought to study cancer cachexia in mice aged to &amp;gt;78 weeks, which corresponds to a human age of greater than 60 years. Our previously published study reported little difference in tumor growth or survival between the two cohorts, yet significant alterations in the muscle transcriptome. Building on this work, we show significant differences in the muscle metabolome of young/aged control and tumor bearing mice. Notably, histamine was higher in aged versus young control mice and even higher in the aged tumor-bearing cohort. We show higher activity of histamine decarboxylase (HDC), the enzyme that converts histidine to histamine in the muscles of aged tumor-bearing mice. Addition of cancer conditioned-media (CM) to C2C12 myotubes was able to induce histamine production and HDC activity in vitro, which demonstrates the ability of muscle cells to induce histamine independent of mast cells. We further show that addition of histamine to myotubes is sufficient to increase atrophy-associated markers. Inhibition of HDC activity by α-fluoromethylhistidine (FMH) in the in vitro model of cachexia protected against myotube thinning. Finally, we treated tumor-bearing aged mice with FMH and observed a) decreased histamine in the muscles 2) decreased HDC activity in the muscles 3) decreased muscle wasting, 4) decreased atrophy markers. Together, we present a novel wasting-associated metabolic pathway and corresponding therapeutic avenue for cancer cachexia that may have been overlooked if not for the use of a more-age-appropriate model of pancreatic cancer. Citation Format: Aneesha Dasgupta, Rebecca E. Schmitt, Jessica Z. Schneider, Tatsuyoshi Kono, Chih-Chun Lee, Carmella Evans-Molina, Jason D. Doles. Targeting differential metabolism in an aged model of cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 356.
Abstract 5994: INX-315, a potent and selective CDK2 inhibitor, demonstrates robust antitumor activity in <i>CCNE1</i>-amplified cancers
Authors: Alec G. Trub, John E. Bisi, Catherine Dietrich, Michael Taylor, Jay C. Strum, Shom Goel, Patrick J. Roberts
Journal: Cancer Research (2023)

Abstract Cyclin-dependent kinases (CDK) are a family of serine/threonine kinases that heterodimerize with regulatory subunits called cyclins to drive cell cycle progression. Uncontrolled cellular proliferation is a hallmark of cancer commonly driven by dysregulated kinase activity of specific CDK family members, including cyclin-dependent kinase 2 (CDK2). Aberrant CDK2 activity most frequently occurs through amplification of CCNE1 and/or overexpression of its protein product cyclin E1, which is a canonical binding partner of CDK2. Overexpression of cyclin E1 is observed in many solid tumors including in patients with high grade serous ovarian cancer (HGSOC), gastric cancer, and ER-positive breast cancer patients whose tumors have progressed on a prior CDK4/6 inhibitor regimen. Selective inhibition of CDK2 is thus a compelling therapeutic approach to regain cell cycle control. Here, we report preclinical data supporting the development of INX-315 for patients with cancers in which proliferation is CDK2-dependent. INX-315 is a potent inhibitor of CDK2/cyclin E (0.6 nM biochemical IC50) with high selectivity over other CDK family members in both biochemical and intracellular NanoBRET assays. In CCNE1-amplified human ovarian and gastric cancer cell lines, INX-315 potently inhibited Rb phosphorylation, induced a G1 cell cycle arrest, and inhibited proliferation. INX-315 also showed potent anti-proliferative activity in luminal breast cancer cell lines that had been cultured in CDK4/6 inhibitor (+/- anti-estrogen therapy) for prolonged periods to the point of developing drug resistance. While these cell lines did not readily respond to either CDK4/6 or CDK2 inhibition alone, combination treatment again suppressed Rb phosphorylation, accompanied by G1 arrest and a senescent-like phenotype. Lastly, in CCNE1-amplified xenograft models of ovarian and gastric carcinomas, INX-315 inhibited Rb-phosphorylation and induced tumor regression. These data demonstrate INX-315 to be a potent and selective CDK2 inhibitor that may benefit patients with CDK2/cyclin E driven cancers. Citation Format: Alec G. Trub, John E. Bisi, Catherine Dietrich, Michael Taylor, Jay C. Strum, Shom Goel, Patrick J. Roberts. INX-315, a potent and selective CDK2 inhibitor, demonstrates robust antitumor activity in CCNE1-amplified cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5994.
Abstract 4564: Liquid-phase-based cell culture platform that enables polymer surface stimuli-induced generation of patient-specific glioma stem cell-like tumor spheroids
Authors: Junhyuk Song, Yoonjung Choi, Yumi Lee, Hyo E. Moon, Changjin Seo, Hyung W. Park, Dohyeon Kim, Chang W. Song, Daeyoup Lee, Sun H. Paek, Sangyong Jon
Journal: Cancer Research (2023)

Abstract Despite the rapidly growing interest on cancer stem cells (CSCs) from cancer biologists, oncologists and the clinic because of their crucial role in recurrence and metastasis due to resistance in solid cancers, including GBM, there is still a lack of robust, effective in vivo-like 3D CSC models from cancer cells or patient-derived tumor tissues. In this sense, we developed a novel functional polymer thin film (Poly-X-PTF) via a streamlined liquid-phase synthesis, a more facile and advanced version than previous lab-made vapor-deposited poly(2,4,6,8-tetravinyl-2,4,6,8-tetramethyl cyclotetrasiloxane) called pV4D4-PTF. Emerging from a previous success with pV4D4, the new platform, Poly-X, could also simply stimulate surface stimuli-guided, rapid transformation of differentiated cancer cells to a number of ECM-enriched, similar-sized 3D CSC-like tumor spheroids from both commercialized cancer cell lines and patient-derived primary GBM cells. Varied GBM patient-derived cancer spheroids demonstrated a variety of phenotypes and transcriptomic profiles known about glioma stem cells (GSCs) in common. Notably, respective sensitivities of different patient-based 3D GSC spheroids to irradiation with or without temozolomide were retrospectively associated with the individual therapeutic outcome and overall survival, as a result of clinically relevant concurrent chemoradiation treatment (CCRT) regimens proposed in a fast Poly-X-spheroids-based 3D viability assay format. Ultimately, this versatile platform may serve to study fundamental CSC biology. Furthermore, it may translate into a powerful preclinical ex vivo tool in glioma medical settings both to aid in on-site prospective prediction of the patient-specific prognosis via CCRT viability responses within around 10 days and assess a patient-tailored, promising drug candidate or combination treatment. Citation Format: Junhyuk Song, Yoonjung Choi, Yumi Lee, Hyo E. Moon, Changjin Seo, Hyung W. Park, Dohyeon Kim, Chang W. Song, Daeyoup Lee, Sun H. Paek, Sangyong Jon. Liquid-phase-based cell culture platform that enables polymer surface stimuli-induced generation of patient-specific glioma stem cell-like tumor spheroids. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4564.
Abstract 1524: Effect of a chimeric antibody targeting CXCL1 in bladder cancer
Authors: Nari Kim, Hideki Furuya, Kaoru Murakami, Charles J. Rosser
Journal: Cancer Research (2023)

Abstract Introduction and Objectives: Chemokine (C-X-C motif) ligand 1 (CXCL1) plays a crucial role in tumor initiation, promotion, and progression in bladder cancer (BCa) development. Previously, we reported on a monoclonal murine antibody (HL2401) towards CXCL1 which was capable of inhibiting growth in both in vitro and in vivo models. Herein, we have developed a chimeric anti-CXCL1 antibody, which is partially human (cHL2401). In this study, we tested the effect of cHL2401 on tumor growth and angiogenesis in both in vitro and in vivo models. Methods: We developed chimeric anti-human CXCL1 antibody (cHL2401), and then tested for the following: ability to inhibit in vitro angiogenesis, ability to inhibit cellular proliferation, and tumor growth in cell line-derived xenograft model. Results: We first performed the tube formation assay to evaluate the effect on angiogenesis. cHL2401 significantly inhibited tube formation in HUVEC, suggesting that cHL2401 inhibits angiogenesis. The inhibitory effect was better than bevacizumab (FDA-approved drug, anti-VEGF antibody). Next, we performed the cell proliferation assay to evaluate the effect on tumor growth in vitro. cHL2401 significantly inhibited the cell proliferation of T24 and 253J cell lines highly expressing CXCL1. Finally, we tested the effect of cHL2401 on tumor growth in an animal model. Both 8 and 32 mg/kg (i.p., twice weekly) significantly inhibited the tumor growth. The final volume of control tumor was 224.5 mm3, while those of 8 and 32 mg/kg were 102.9 and 93.08, respectively. Conclusions: The chimeric antibody, cHL2401 contains human constant domains and mouse variable domains of mouse HL2401 antibody. Species-matched chimeric antibodies reduce anti-species immune responses in animal models. In this study, we tested whether the effects of mouse HL2401 that we have reported were induced by neutralizing CXCL1 by antibody. Taken together, the results suggest that neutralizing CXCL1 by antibody could be a promising therapeutic agent in BCa. Citation Format: Nari Kim, Hideki Furuya, Kaoru Murakami, Charles J. Rosser. Effect of a chimeric antibody targeting CXCL1 in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1524.
Abstract 5571: FoxP3 absolute quantification to build an effective risk model for cancer patient survival
Authors: Adele Ponzoni, Sandra Delebecq, Melodie Boute, Corinne Ramos, Jonathan Stauber
Journal: Cancer Research (2023)

Abstract Background: Forkhead box protein P3 (FOXP3), belonging to the forkhead/winged-helix family, is of great importance in modulating the differentiation and development of T-regulatory cells (Tregs). The numbers of FOXP3+ Tregs as well as exhaustive subsets of CD4+ and CD8+ T cells have been observed increased in solid tumor tissues of patients with colorectal and breast cancers, which helps to create an immunosuppressive environment and promotes tumor progression. However, the correlation between the presence of FOXP3+ Tregs and patients’ survival has been extensively studied in many cancer types, which remains conflicting. The approach presented here aims to absolutely quantify the level of FOXP3 in single cells and constructed effective immune risk models to predict tumor prognosis. Method: Imaging mass cytometry (IMC) was used to quantify FOXP3 inside each single cell. The indirect quantification used a free-metal titration curve in order to match the level of intensity of the metal-tagged antibodies to the level of expression of the antigen. Deep learning (StarDist QuPath extension) was used for cell segmentation and expression quantification. FOXP3 quantification in tissue or at the single cell level was validated against ELISA assay that measure FOXP3 in tissue lysate. Results: Linearity of the metal signals with an average %CV of 17% was observed emphasizing the linear correlation between free metal concentration and intensity. With the IMC technique, the minimum amount of FoxP3 detectable is 0.09 femtogram and its absolute quantification in the different cells in tumor tissues was confronted to disease prognosis in order to start building an effective immune risk model. Conclusion: With the introduction of new biologics in cancer therapy, it is imperative to follow real quantitative change in the expression of biological marker that are indicator of tumor prognosis. Indeed, although the FOXP3 distribution was already seen to be heterogenous in tumors, its absolute level of expression indicative of disease progression can be directly correlated to gain better understanding of the patient response stratification to biologics. Citation Format: Adele Ponzoni, Sandra Delebecq, Melodie Boute, Corinne Ramos, Jonathan Stauber. FoxP3 absolute quantification to build an effective risk model for cancer patient survival. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5571.
Abstract 4006: TRX-221, a novel 4th-generation EGFR inhibitor for overcoming C797S mutation-mediated acquired resistance in NSCLC
Authors: Sumin Lim, Seulgi Choi, Ju-Kyung Lee, Eunhyun Choi, Sungwon Lee, Kwangwoo Chun, Myoungki Baek, Jiyeon Park, Jihyun Kim, Areum Kang, Younghoon Kim, Namkyoung Kim, Byoungchul Cho, Taebo Sim, Koo Lee
Journal: Cancer Research (2023)

Abstract Targeting mutated EGFR is a clinically validated approach for tackling non-small cell lung cancer (NSCLC). Approximately 20% of patients with advanced NSCLC harbor an EGFR mutation. Osimertinib is a 3rd-generation oral EGFR-TKI targeting the EGFR sensitizing mutations Del19 and L858R, as well as an acquired mutation, T790M. Despite osimertinib's efficacy in NSCLC, resistance develops and the mechanisms of resistance to osimertinib are complex. Development of another mutation, C797S is the most common mechanism of acquired resistance following osimertinib treatment. This mutation occurs with about 12% frequency after a 1L therapy of osimertinib, and with approximately 17% frequency after a 2L therapy. Here, we report TRX-221 as a novel 4th-generation EGFR-TKI that can overcome C797S-mediated acquired resistance in NSCLC models in vitro and in vivo. TRX-221 exhibited potent inhibitory activity against multiple EGFR mutant kinases, including Del19/T790M/C797S, L858R/T790M/C797S, Del19/C797S, L858R/C797S, Del19/T790M, L858R/T790M, Del19, and L858R. Likewise, TRX-221 potently inhibited the proliferation of Ba/F3 cells stably overexpressing these eight EGFR mutants. TRX-221 however showed sparing activity against EGFR wild-type kinase and cell lines. TRX-221 also demonstrated marked anti-proliferative activity against osimertinib-resistant patient-derived cancer cell lines (PDCs). With favorable DMPK profiles, once-daily oral dosing of TRX-221 induced strong anti-tumor effects in a dose-dependent manner in a variety of osimertinib-resistant CDX and PDX models. As a reversible, selective, and broad-spectrum 4th-generation EGFR-TKI, TRX-221 is currently undergoing IND-enabling studies and shows strong potential as a therapeutic solution to treat advanced NSCLC patients harboring EGFR mutations. Citation Format: Sumin Lim, Seulgi Choi, Ju-Kyung Lee, Eunhyun Choi, Sungwon Lee, Kwangwoo Chun, Myoungki Baek, Jiyeon Park, Jihyun Kim, Areum Kang, Younghoon Kim, Namkyoung Kim, Byoungchul Cho, Taebo Sim, Koo Lee. TRX-221, a novel 4th-generation EGFR inhibitor for overcoming C797S mutation-mediated acquired resistance in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4006.
Abstract 4593: Glioblastoma tumors that respond poorly to bevacizumab therapy show upregulation of an angiogenesis gene set
Authors: Roshan Lodha, Gaelle Muller-Greven, Lydia Guo, Candece Gladson
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) is the most common primary brain tumor in adults with a 15-month median survival, despite surgical-resection and radio-chemotherapy, and a recurrence rate of 90%. Despite improving survival in only a small percentage of patients, bevacizumab, a monoclonal antibody toward vascular endothelial growth factor-A, is frequently used to treat recurrent-GBM. To find predictors of poor-response to bevacizumab, we performed RNA-sequencing on multiple GBM patient-derived xenograft (PDX) tumors after orthotopic propagation in athymic nude mice. The study was repeated, and once PDX-tumors were established, mice were treated with bevacizumab and grouped based on survival. Bioinformatic-analysis of RNA-sequencing data demonstrated differential gene expression in tumors that were poor-responders to bevacizumab (no survival change) as compared to tumors that were good-responders (longer survival), along with upregulation of an angiogenesis gene set in poor-responders. Within this gene set, multiple genes known to be regulated by the early growth response 1 (EGR1) transcription factor were identified; CHRNA7 (cholinergic-receptor-nicotinic-α7-subunit) was selected for further study based on the reported role in promoting cancer cell migration and proliferation. Results were validated at the protein level using immunohistochemical staining. Additionally, Sry-box transcription factor-10 (SOX10) showed upregulation in poor-responders, potentially driven by impaired proteosome degradation. SOX10 is known to promote mural-cell coverage of neovasculature, cancer cell migration, and glioma development when cooperating with platelet-derived growth factor-B (PDGFB). In summary, GBM PDX-tumors with upregulated expression of an angiogenesis gene set and of two transcriptional regulators (EGR1 and SOX10) demonstrated a poor response to bevacizumab; upregulation of these genes could be used to predict bevacizumab response. Citation Format: Roshan Lodha, Gaelle Muller-Greven, Lydia Guo, Candece Gladson. Glioblastoma tumors that respond poorly to bevacizumab therapy show upregulation of an angiogenesis gene set. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4593.